N-(2-carbamylalkyl)-aralkylamines



Unite grates 2,886,594 Patented May 12, 1959 free 2,ss6,594 N-(2CARBAMYLALKYD-ARALKYLAMENES Alexander R. Surrey, Albany, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application December 27, 1954, Serial No. 477,935, now Patent No. 2,776,991, dated January 8, 1957. Divided and this application Septernher 29, 1955, Serial No. 537,552

6 Claims. (Cl. 266-558) This invention relates to certain N-(2-carbamylalkyl)- (substituted-phenyl)alkylarnines used for example as intermediates in the preparation of preferred embodiments of my copending application Serial No. 477,935 (filed December 27, 1954; now US. Patent 2,776,991, issued January 8, 1957), of which this application is a division.

The N aralkyl-N-(2-carbamylalkyl)-halogenated-al kanamides which are disclosed and claimed in US. Patent 2,776,991 have the general formula where Ar is a member selected from the group consisting of phenyl, naphthyl, biphenylyl, furyl, pyridyl and thienyl radicals, X is a lower alkylene radical having from one to four carbon atoms, Y is a lower al.pha,beta-alkylene radical having from two to four carbon atoms, R is a member selected from the group consisting of hydrogen and a hydrocarbyl radical having from one to eight carbon atoms, and Ac is a halogenated-'(lower alkanoyl) radical having from two to four carbon atoms. Chemotherapeutic evaluation of these compounds has shown them to possess amebacidal activity.

The lower alkylene radical X has from one to four carbon atoms, and includes such examples as and the like The lower alpha,beta-alkylene radical Y has from two to four carbon atoms, and includes such examples as and the like.

The hydrocarbyl radical R has from one to eight carbon atoms, and can be alkyl, alkcnyl, cycloalkyl, cycloalkylalkyl, phenyl, alkylated-phenyl, benzyl or phenethyl, and includes such examples as: methyl, ethyl, n-propyl, isopropyl, 2-butyl, isoarnyl, n-hexyl, and the like, when alkyl; Z-propeuyl, 3-butenyl, 4-hexenyl, and the like, when alkenyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, when cycloalkyl; cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like, when cycloalkylalkyl; Z-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3ethylphenyl, and the like, when alkylatedphenyl.

The halogenated-(lower alkanoyl) radical Ac has from two to four carbon atoms, and includes such examples as chloroacetyl (chloroethanoyl), iodoacetyl, fluoroacetyl, dichloroacetyl (dichloroethanoyl), dibromoacetyl, trichloroacetyl, Z-chloropropanoyl (alpha-chloropropionyl), 3-bromopropanoyl, 2,2-diiodopropanoyl, 2bromo-3-chloropropanoyl, 2,2-dichloropropanoyl, 2,2-difluoropropanoyl, 2,2,3-trichloropropanoyl (alpha,alpha,beta-trichloropropionyD, 2-chlorobutanoy1 (alpha-chlorobutyryl), 3- bromobutanoyl, 2,2-dichlorobutanoyl, 3,4-dibromobutanoyl, 2,2,3-trichlorobutanoyl, 2,3,4-trichlorobutanoyl, and the like.

The compounds of my US. Patent 2,776,991 were prepared by reacting an N-(Z-carbamylalkyl)-aralkylamine of the formula, ArX-NH-Y-CONHR, with an acylating agent selected from the group consisting of those having the formulas, Ac-halogen and (Ac) 0, where Ar, X, Y, R and Ac have the meanings given above. When a halogenated-alkanoyl halide, Ac-halogen, was used, the halide halogen, i.e., the halo radical attached to the carbonyl function, was preferably chloro, however, the other halo radicals, i.e., bromo, iodo and fluoro also can be used.

The N-(2-carbamylalkyl)-aralkylarnines of this invention where R is hydrogen, i.e., ArXNHY-CON H were prepared by reacting an aralkylamine of the formula, ArX-NH where Ar and X have the meanings given above, with a Z-alkenamide. This preparation was carried out, preferably, by: warming the reactants gently until solution was complete; allowing the reaction mixture to stand at room temperature from one to two weeks; dissolving the reaction mixture in an appropriate solvent, e.g., acetone; and treating the resulting solution with ethanolic hydrogen chloride to precipitate the N- (Z-carbamylalkyl)-aralkylamine in the form of its hydrochloride. lllustrations of the preparation of these N(2- carbamylalkyl)-arall;ylamines, each in the form of its hydrochloride, are: the preparation of N-(2-carbamylethyl)-2,4-dichlorobenzylamine by reacting 2,4-dichlorobenzylamine with acrylarnide; the preparation of N-(2- carbarnylpropyl)-3,4,5-tribromobenzylamine by reacting 3,4,S-tribromobenzylamine with alpha-methylacrylamide; and the preparation of N(2-carbamylbutyl)-4-nitrophenethylamine by reacting 4-nitrophenethylamine with alpha-ethylacrylamide.

The N-(2-carbarnylalkyl)-aralkylamines where R is a hydrocarbyl radical, i.e., Ar-XNHYCONH hydrocarbyl, were prepared by first reacting an aralkylamine of the formula, ArX-NH where Ar and X have the meanings given above, with a lower alkyl ester (preferably the methyl ester) of a Z-alkenoic acid, and then reacting the resulting N-(Z-carbalkoxyalkyl)-aralkylamine with a hydrocarbyl primary amine, RNH Illustrations of this procedure are: the preparation of N- [2 (ethylcarbamyl) ethyl] -2,4-dichlorobenzylamine" by carbamylalkyl)halogenated-alkanamides having the formula where X, Y, R and Ac have the meanings given above,

the i where X, Y, R, Z and m have the meanings given in the immediately preceding paragraph.

The following examples will further illustrate specific embodiments of the invention without, however, limiting it thereto.

EXAMPLE 1 N (2 -carbamylalkyl -ai-alkylamines The preparation of the intermediate N(2-carbamylalkyl)-aralkylamines having the above formula where R is hydrogen is illustrated by the following preparation of N-(Z-carbamylethyl)-4-chlorobenzylamine: A mixture of 28.3 g. of 4-chlorobenzylamine and 15.6 g. of acrylamide was warmed gently until solution was complete, and then left at room temperature for 7 days. The resulting solid was taken up in 400 ml. of acetone and N ethanolic hydrogen chloride was added in 10 ml. portions. The precipitate was collected from each fraction before the following portion of acid was added. There was thus obtained two fractions weighing g. and 9 g., respectively, which were combined and recrystallized twice from isopropanol, yielding the desired intermediate, N-(Z-carbamylethyl)-4-chlorobenzylamine in the form of its hydrochloride, M.P. 220.1221.2 C. (corn).

Analysis.Calcd. for c H c1N oHc1: Cl 14.24; N, 11.25. Found; Cl, 14.33; N, 11.26.

Other N-(Z-carbamylethyl)-aralkylamine hydrochlorides that were prepared following the procedure described above for the preparation of N-(2-carbamylethyl)- 4-chlorobenzylamine hydrochloride using the appropriate aralkylamine and 2-alkenarnide are given in Table I.

TABLE I Hydrochloride, M .P., O.

217418.23 (corr.). 164.5-166.

21S.9220.8 (corn).

1813-1827 (corn) mom. H

The free base form of these compounds was obtained by treating an aqueous solution of the hydrochloride with alkali, extracting the liberated base with benzene, removing the solvent by distilling in vacuo and recrystallizing the resulting N -(2carbamyletl1yl)-aralkyiamine from an appropriate solvent.

This compound was used directly in the next step.

di-chlorophenyl)butylamine, N-(Z-carbamylbutyl)-4-di-nbutylaminobenzylamine, N (Z-carbamylethyl)-4-n-hexoxybenzylamine, N- (Z-carbamylethyl) -4-n-butylmercaptobenzylamine, N(2-carbamylethyl)-4-n-butylsulfonylbenzylamine, N-(2-carbamy1ethyl)-4-nitrobenzylamine, N-(2- carbamylethyl) 2 furylmethylamine, N-(Z-carbamylethyl) -2-thienylmethylamine, N-(2-carbamylethyl) -2-pyridylmethylamine, N-(2-carbamylethyl)-3-pyridylmethylamine, N-(2-carbamylpropyl)-5-chloro-2-pyridylmethylamine, and the like.

EXAMPLE 2 A. N-(2-carbalk0xyalkyl) -aralkylamines The preparation of these intermediate N-(2-carbalkoxyalkyl)-aralkylamines is illustrated by the following preparation of N-(Z-carbomethoxyethyl)-4-isopropylbenzylamine: To 43 g. of methyl acrylate was added 60 g. of 4-isopropylbenzylamine with stirring and occasional cooling, keeping the temperature below 35 C. The reaction mixture was then allowed to stand for one week at room temperature. The excess methyl acrylate was removed by distilling under reduced pressure and the residual material distilled in vacuo. The fraction boiling at -135 C. at 0.3 mm. was the desired product, N- (2 carbomethoxyethyl)-4-isopropylbenzylamine, n 1.5030.

Analysis.Calcd. for C H NO N 5.95. Found: N 5.92.

Here N means basic nitrogen content as determined by acetic acid-perchloric acid titration.

Other N-(Z-carbalkoxyalkyl)-aralkylamines that are prepared according to the above procedure are: N-(2- carbethoxyethyl)-2,4-dichlorobenzylamine, N-(Z carbomethoXypropyl)-4-n butoxybenzylamine, N (2 carbomethoXybutyl)-3,4 diethoxybenzylamine, N (2 carbomethoxyethyl)-4-n-hexylbenzylamine, and the like.

B. N [2- (hydrocarbyl-carbamyl alkyl -aralkylamines The preparation of these intermediate compounds is illustrated by the following preparation of N-[2-(ethylcarbamyl)ethyl]-4-isopropylbenzylamine: A mixture of 23.5 g. of N-(2-carbomethoxyethyl)-4-isopropylbenzylamine, 45.1 g. of anhydrous ethylamine and 50 ml. of ethanol were left tightly stoppered at room temperature for five days. The solvent and excess ethylamine were removed by distilling under reduced pressure, and the resulting viscous red oil was distilled. The fraction boiling at -148 C. at 1 micron, 11 1.5204, was the desired product, N [2-(ethylcarbamyl)ethy1]-4-isopropylbenzylamine.

Analysis.Calcd. for C H N O: N 5.62. Found: N 5.64.

Following the above procedure but substituting for ethylamine, n-hexylamine, allylamine, cyclopentylamine, cyclohexylmethylamine, aniline, 3-ethylaniline, benzylamine or phenethylamine, and using the appropriate N- (Z-carbalkoxyalkyl)-aralkylamine, the following products are obtained: N-[2-(n-hexylcarbamyl)ethyl]-4-isopropylbenzylamine, N [2 (allylcarbamyl)ethyl]-2,4-dichlorobenzylamine, N- [2- cyclopentylcarbamyl) propyl] 4 n butoxybenzylamine, N [2 (cyclohexylmethylcan bamyl)ethyl]-3,4-dibromobenzylamine, N [2 (phenylcarban1yl)butyl]-4 chlorobenzylamine, N-[2 (3 ethylphenylcarbarnyl)ethyl] 2 (3,4 diethoXyphenyDethylamine, N [2 (benzylcarbamyl)ethyl] 2,4 dichlorobenzylamine or N-EZ-(phenethylcarbamyl)ethyl]-4-nitrobenzylamine.

I claim:

1. A compound having the formula where Z is a member selected from the group consisting of halo and lower alkoxy, m is an integer from one to 5 three inclusive, X is a lower alkylene radical having from one to four carbon atoms, Y is a lower alpha, beta-alkylene radical having from two to four carbon atoms and R is a member selected from the group consisting of hydrogen and an alkyl radical having from one to eight carbon atoms. v

2. A compound having the formula (halogen) CH -NHCH CH C ONH,

(halogen) 3. A compound having the formula (halogen) -CH;NHCH CH C ONE,

4. A compound having the formula (lower alkoxy) cn Nflcmcmc oNH,

(lower alkoxy) 5. A compound having the formula (lower alkoxy) CHr-NECH5GH3C ONE 6. N-(Z-carbamylethyl)-2,4-dichlorobenzylamine.

References Cited in the file of this patent UNITED STATES PATENTS Leuchs May 4, 1943 Lofgren et a1 May 11, 1948 Goldberg et a1 Oct. 23, 1956 Brandstrom et a1. July 1, 1958 FOREIGN PATENTS Belgium Sept. 13, 1952 Great Britain Mar. 26, 1947 Great Britain Apr. 18, 1947 

1. A COMPOUND HAVING A FORMULA
 6. N-(2-CARBAMYLETHYL)-2,4-DICHLOROBENZYLAMINE. 